DESCRIPTION: Applicant's Abstract Human T-cell lymphotropic viruses type I (HTLV-I) and type II (HTLV-II) are two closely related retroviral pathogens of emerging significance among intravenous drug users (IDU). The rate of infection is 20% in this at risk population with seroprevalence ranging widely from region to region, 0.4 - 20 %, in the United States. The majority of IDU are infected with HTLV-II (84%) and the remaining infected with HTLV-I. Unfortunately, the infection rate is likely to increase in IDU as documented rather dramatically in a number of studies from Spain and Sweden. The project is to continue the detailed analysis of the humoral immune response to HTLV-1 and HTLV-II among IDU. To date, we succeeded in producing an extensive panel of human monoclonal antibodies (HMAbs) to virtually all HTLV structural proteins from peripheral B-cells of an infected IDU and other individuals. The molecular and biochemical characterizations of viral epitopes identified by these HMAbs have led to the development of better diagnostic tools for HTLV-I and -II disease association studies which has contributed to the recognition of HTLV-II associated neurological disorders. The functional characterization of these antibodies has identified HTLV conformational epitopes mediating virus neutralization. With these tools in hand and mounting evidence of HTLV-II neurological disease association that are already well-established with HTLV-I, we will explore the involvement of viral proteins in spontaneous T-cell activation observed in some infected individuals and their immune response to these proteins during the disease course as possible risk factors for HTLV neuropathy. The contribution of co-infection with HIV will be assessed since many IDU are infected with both viruses. Our premise is that virus encoded proteins expressed on the surface of infected cells are potential mediators of HTLV-induced T-cell activation and proliferation. Through these studies and the continuation of our effort to define the protective immune response to HTLV, we will gain further insights in HTLV pathogenesis and ultimately, in the design of anti-HTLV-I and -II therapies as well as potential vaccines.